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MXPA05005580A - Isoindoline derivative. - Google Patents

Isoindoline derivative.

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Publication number
MXPA05005580A
MXPA05005580A MXPA05005580A MXPA05005580A MXPA05005580A MX PA05005580 A MXPA05005580 A MX PA05005580A MX PA05005580 A MXPA05005580 A MX PA05005580A MX PA05005580 A MXPA05005580 A MX PA05005580A MX PA05005580 A MXPA05005580 A MX PA05005580A
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Mexico
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compound
group
dimethyl
alkyl
further characterized
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MXPA05005580A
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Spanish (es)
Inventor
Takashi Tamura
Original Assignee
Maruishi Pharma
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/64—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Engineering & Computer Science (AREA)
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  • Anesthesiology (AREA)
  • Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

A novel isoindoline compound represented by the formula (I). (I) The compound has sedative activity. The compound leads mammals to sedation and is hence useful as a narcotic drug.

Description

DK, DM, DZ, EC, EE, 1; G, ES, FI, GB. GD, GE, Gil. GM, FR, GB, GR, HU, IB, IT, LU, MC, NI., PT, RO, SE, YES, SK, HR, I TU, ID, IL, IN, IS, JR Kfi, KG, KR , KZ, LC, LK, LR, TR), OAPI ???? (BF, BJ, CE CG, CI, CM, GA, GN, GQ, LS, LT, LU, LV, ??, MÜ, MG, MK, MN, MW, MX, MZ, GW, ML, MR, NE , SN, TD, TG). NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, ??, TZ, UA, UG , US, uz, VC, VN, YU, ZA, ZM, ZW. (84) 1 DERIVATIVES OF ISOINDOLINE FIELD OF THE INVENTION The present invention relates to new isoindoline derivatives. The derivatives of the invention are useful for preparing pharmaceutical compositions, especially anesthetics.
RELATED TECHNIQUE It has been reported that many compounds having an isoindoline structure have effects on the central nervous system. Most of these reports were aimed at developing tranquilizers, antispasmodics or anxiolytics (published Japanese patent applications Nos. 47-12322 and 58-189163). So far no isoindoline derivative having anesthetic properties has been reported. For agents that affect the CNS, especially intravenous anesthetics, a rapid induction and recovery of anesthesia is desired. To prepare an injectable dosage form, it is also desired that the anesthetic compounds be soluble in water. However, clinically-used anesthetic compounds, for example, propofol (2,6-diisopropylphenol), are slightly soluble in water and therefore, intravenous anesthetics used clinically are provided in the form of an anesthetic. emulsion with soybean oil, glycerin and purified egg phospholipid. Due to this formulation, clinical endovenous products have side effects such as venous pain during injection and lipid deposition as well as high susceptibility to microbial infection. Up to now, no active agent has been reported with respect to the CNS that is sufficiently soluble or miscible in water, as well as that does not induce, or induces few, side effects.
BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide a new water-soluble or water-miscible compound useful for making an anesthetic, especially an intravenous anesthetic. The present invention provides a compound represented by the formula (I): wherein the R- \ are the same or different groups 1 -3, each being selected from the group consisting of C1-3 alkyl and C1-3 alkoxy, or when the Ri are two adjacent groups, the two Ri taken together can form a cyclic group of 5 or 6 members, saturated or unsaturated, which can have 1 or 2 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen; X is oxygen or sulfur; R 2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which may be optionally substituted; as long as R2 is phenyl, the 3 and 4 positions of the phenyl part are not simultaneously substituted by alkoxy groups; represents a simple link or a double link; and L is - (CH2) n-H wherein n is an integer of 1-8; wherein R3 is selected from the group consisting of hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atom, cyclopentyl, cyclohexyl, cycloheptiio, cyclohexylmethio, benzyl, 2-pyridyl and pyrimidinyl, n 'is an integer of 1-3; - (CH2) n- C- A W wherein W is an oxygen or sulfur atom, A is selected from the group consisting of linear or branched C1-5 alkyl, 2-4 dimethylaminoethylamino, 2-thiazolylamino, 4-methylhomopiperazinyl, 4-piperidinopiperidino, dimethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonylpiperidino, 4-carboxypiperidone and a group represented by the formula (J) where R3 is as defined above, n "is an integer of 0-3; ^ CH2) n-C-OE O wherein E is selected from the group consisting of hydrogen, alkenyl or straight or branched C1-6 alkyl, C1-3 alkyl substituted by at least one fluorine atom, 2-methoxyethyl, 2- methylthioethyl, 2-dimethylaminoethyl, phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, cyclohexylmethyl, 1-methyl-4-piperidinyl, indanyl, 1,3-benzodioxolyl and 1H-indolyl, in where phenyl and pyridyl may be optionally substituted by the group consisting of halogen, methyl, methoxy, isopropyl and allyl, provided that when Ri is 7-methoxy and R 2 is phenyl, E is not alkyl, n "is an integer of 0-3; - (CHzJn-T- 3 where T is oxygen, sulfur or NH, G is selected from the group consisting of hydrogen, C1-5 linear or branched alkyl, C1-3 alkyl substituted by at least one fluorine atom, 2-methoxyethyl and alkylcarbonyl, n 'an integer of 1-3; wherein R3 is as defined above; wherein R3 is as defined above; - OCH5-C-OE 2 II or wherein E is as defined above; wherein R3 is as defined above; or = CH- C-OE II OR where E is as defined above; or a salt of it. 6 The compound of the present invention can induce an excellent sedative action in a mammal and is therefore preferably used to make an anesthetic. The present invention further provides an anesthetic composition for inducing a sedative and anesthetic effect in a mammal comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The anesthetic composition of the invention is especially useful as an intravenous anesthesia. Additionally, the present invention provides the use of the compound of the formula (I) or a pharmaceutical salt thereof to make a pharmaceutical composition for inducing a sedative and anesthetic effect in a mammal. In addition, the present invention provides a method for providing anesthesia in a mammal requiring anesthesia, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. In the present description and in the claims, the compound is described using the isoindoline (I) backbone numbering system shown below, unless there is a specific indication. 7 In the present description and in the claims, the definitions of L are described with or without the bond between the isoindoline backbone. The definition with the link defines "1_", and the one without the link defines "L".
DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment of the present invention the Ri of the formula (I) may be one or two groups, which may be the same or different, and are selected from the group consisting of methyl, ethyl and methoxy. The number of R-i is preferably 2. Especially the 5,6-dimethyl compound, that is, the compound of the formula (I) wherein the two positions 5 and 6 are substituted by methyl. In another preferred embodiment of the invention, two R-i at positions 5 and 6 of the isoindoline structure taken together form a 5-membered cyclic group which may have one or two oxygen atoms. X represents oxygen or sulfur, and oxygen is preferred. R 2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which can be optionally substituted. When R2 is phenyl, the 3 and 4 positions of the phenyl are not substituted by alkoxy groups simultaneously. For R 2, optionally substituted phenyl and optionally substituted pyridyl and optionally substituted pyridyl are especially preferred. R2 may optionally have 1-3, more preferably 1 or 2 substituents. Examples of substituents may include halogens, such as, fluorine, chlorine, bromine and iodine, hydroxy, C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl, C 1-4 alkoxy, such as, methoxy, ethoxy, propoxy, isopropoxy and butoxy, trifluoromethyl, C 1-3 alkyl substituted by at least one atom of fluorine, such as, trifluoromethoxy, trifluoroethoxy and trifluoropropoxy, amide, carboxy, cyano, C1-4 alkylthio, such as ethylthio, propylthio and butylthio, nitro, amino, methylamino, dimethylamino, dimethylaminomethyl, dipropylaminomethyl, methylenedioxy, phenoxy, benzyloxy, alkanoyloxy C2-5, such as acetoxy, propionyloxy and butyryloxy,? -hydroxyalkyl C1-3, such as, hydroxymethyl and hydroxyethyl, C2-5 alkanoyloxy-C1-3alkyl, such as acetyloxymethyl, acetyloxyethyl and propionyloxyamino; C2-5 alkanoylamino such as acetylamino and propionylamino; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl. When R2 has a substituent, the substituent may be at any position of R2. When R2 is phenyl, the phenyl part preferably has no substituent or has a fluorine substituent in the 3 or 4 position, of 9.C1-4 alkoxy in the 4-position, of alkoxycarbonium, methylamino or dimethylamino in the 3-position. When F¾ is pyridine, a substituent is not preferred. According to the present invention, when L is - (CH2) n "- C - A ww represents oxygen or sulfur and oxygen is preferred, A is selected from the group consisting of linear or branched C1-5 alkyl, 2-dimethylaminoethylamino, 2-thiazolylamino, 4-methylhomopiperazinyl, -piperidinopiperidino, dimethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonylpiperidino, 4-carboxypiperidino and a group of the formula (J): when A is (J), examples of R 3 may include hydrogen, linear or branched C 1-8 alkyl, substituted by at least one fluorine atom, such as 3,3,3-trifluoropropyl, cyclopentyl, cyclohexyl, cycloheptyl. , cyclohexylmethyl, benzyl, 2-pyridyl and 2-pyrimidinyl. The preferred A is C1-5 alkyl, especially linear alkyl, or the group of formula (J), especially the group (J) wherein R3 is methyl or isopropyl. n "is preferably 1 or 2 and especially 1. According to the present invention, when L is 10 - (CH2) n- C- OE O E is selected from the group consisting of hydrogen, alkenyl or straight or branched C 1-6 alkyl, C 1-3 alkyl substituted by at least one fluorine atom, such as, 3,3,3-trifluoropropyl, 2-methoxyethyl, 2- methylthioethyl, 2-dimethylaminoethyl, phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, cyclohexylmethyl, 1-methyl-4-piperidyl, indanyl, 1,3-benzodioxolyl and 1H-indolyl. When Ri is methoxy in the 7-position of the isoindoline (7-methoxy) structure and F¾ is phenyl, E is not an alkyl. When E is phenyl or pyridyl, it may be substituted by halogen, methyl, methoxy, isopropyl or allyl. When E is an alkyl, propyl and isobutyl are preferred. Preferably E also includes phenyl substituted by methyl and / or methoxy. n "represents an integer of 0-3 and especially 1 or 0. When L is - (CH2) nTG, n 'is an integer of 1-3 preferably 2. T is oxygen, sulfur or NH, especially oxygen or sulfur is preferred. G is selected from the group consisting of hydrogen, linear or branched C 1-5 alkyl, C 1-3 alkyl substituted by at least one fluorine atom, 2-methoxyethyl and alkylcarbonyl, especially ethyl and propyl. eleven In accordance with the present invention, especially preferred compounds are the following: where R2 and L are selected from the combinations shown below: 12 13 R2 In addition to those indicated above, the compound of any of the formulas indicated above is also preferably used wherein F¾ is: wherein R 4 is selected from the group consisting of C 1-5 alkyl, optionally substituted phenyl and optionally substituted benzyl, and L is: Examples of substituents on the phenyl or benzyl of R 4 may include halogen, methyl, methoxy, isopropyl and allyl. Preferably R4 is alkyl or phenyl.
Synthesis of the compound The methods for synthesizing the compound of the invention are illustrated below. The methods indicated below are only examples and the compound of the invention can be prepared by any of the known methods. • Compound of formula (I) where L is: - (CH2) n- C-OE Wherein n "and E are as defined above can be prepared, for example, by hydrolyzing compound (II): fifteen wherein i and R2 are as defined above, Z is COOCH2CH3 or CN and then, if desired, esterifying the carboxylic acid obtained. More precisely: (1) compound of formula (II) wherein Z is a carboxyl group, such as formula (11-1): wherein R-i, R2 and n "are as defined above can be prepared according to the method described below: i) the compound wherein n" = 1 can be prepared according to the scheme shown below: (ll-a) (I a) (R1 and R2 are as defined above). Method for preparing the starting material of formula (III): The 3,5-dimethylphthalic anhydride (111-1) can be prepared by heating the mixture of 4,6-dimethyl-2-pyrone and chloro maleic anhydride. 4,5-Dimethylphthalic anhydride (IH-2) can be prepared by heating the acid anhydride, which is obtained by reacting 2,3-dimethyl-1,3-butadiene and maleic anhydride, in acetic acid together with bromine. The 3,4-dimethylphthalic anhydride can be obtained from 3-methyl-1,3-pentadiene and maleic anhydride in the same manner as the compound (III-2). The 3,6-dimethyl-phthalic anhydride can be obtained according to J. Amer. Chem. Soc, 66, 733 (944). 4,5-Diethylphthalic anhydride (III-3) can be prepared by converting the dicyan compound obtained according to J. Heterocyclic Chem. 22, 575 (1985) into the corresponding dicarboxylic acid with sulfuric acid followed by dehydration (cyclization) with anhydride. acetic. The 4,5-dimethoxyphthalic anhydride (III-4) can be prepared by heating the 3,4-dimethoxybenzoic acid in formalin saturated with hydrogen chloride gas to give the corresponding lactone, converting the lactone into dicarboxylic acid with sodium hydroxide and permanganate of potassium followed by dehydration (cyclization) with acetic anhydride. The 5,6-indanedicarboxylic anhydride (III-5) can be prepared by reacting 1,6-heptadiino and diethyl acetylenedicarboxylate to give the diester compound, converting the diester compound to the 17-hydroxy compound. dicarboxylic acid with hydrochloric acid followed by dehydration (cyclization) with acetic anhydride. 5,6,7,8-Tetrahydro-2,3-naphthalene-dicarboxylic anhydride and 1,3-dihydro-2-benzofuran-5,6-dicarboxylic anhydride can be prepared from 1 to 7 -octdiin and propargyl ether respectively in the same manner as the compound (III-5). The 1,3-benzodioxol-5,6-dicarboxylic anhydride can be obtained from 1,2-dibromo-4,5- (methylenedioxy) benzene in the same manner as the compound (III-3). 18 The appropriate starting compound (III) thus obtained is heated in acetic acid or dimethylformamide with an amine compound of the formula: R2-NH2 (wherein R2 is as defined above) to give the compound (IV). According to the method described in published Japanese patent application No. 58-189163, the compound (IV) is reduced with sodium borohydride in a mixed solution of methanol and tetrahydrofuran to give the compound (V) and the compound (V ) in toluene is heated with Ph3P = CHCOOCH2CH3 to give the compound (I la), and then the compound (II-a) is hydrolyzed to give the compound (11-1 a). ii) Compound of formula (11-1 b) (compound of formula (11-1) wherein n "= 2) Compound (11-1 b) can be obtained according to the scheme as shown below using the compound (ll-a) (n "= 1) as a starting material. ("-b) (lUb) 19 [In the scheme above, Ri and F½ are as defined above, Ms represents a methanesulfonyl group]. According to the method described in published Japanese patent application No. 58-189163, the compound (ll-a) in tetrahydrofuran is reduced with lithium borohydride to give the compound (VI), then reacted with methanesulfonyl chloride to give the mesylated compound (VII). The compound is then heated with potassium cyanide in aqueous ethanol to give the compound (ll-b) and hydrolyzed with an acid to give the compound (11-1 b) where n "is 2. When F¾ is a pyridyl group , the compound (ll-a) can be reduced by heating the compound in methanol with excess sodium borohydride iii) n "= 0 The compound (ll-1c), or the compound (11-1) where n" = 0, can be obtained according to the scheme shown below using the compound (III) shown above as a starting material. twenty [Ri and R2 are as defined above]. The compound (III) is reduced with lithium tri-tert-butoxyaluminohydride according to Tetrahedron, 24, 2443 (1968) to give the compound (III-a), and then it is converted into (lll-b) according to Aust. J. Chem., 34, 151 (1981). The compound (lli-b) is reacted with an amine compound R2-NH2 [wherein R2 is as defined above] to give the compound (III-c). The compound (III-c) thus obtained is reacted with cyanoethylsilane according to J. Org. Chem., 54, 2417 (989) to effect the cyclization and the compound (ll-c) is obtained. The compound (ll-1c) is then obtained by hydrolyzing the compound (ll-c) with an acid. (2) compound (II-2) [R1 and R2 are as defined above, E is as defined above with the exception that E is not hydrogen]. The compound (II-2) can be obtained by reacting a carboxylic acid compound (11-1) with a correspog alcohol, phenol or hydroxyl compound in the presence of WSC [1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride] and DMAP (4-dimethyaminopyridine). The compound of formula (I) wherein L is: 21 or the compound (II-3): wherein Ri, R2, A and n "are as defined above is prepared by the following methods: The compound (II-3) wherein A is not an alkyl group can be prepared by reacting the carboxylic acid compound (11- 1) with a correspog amine compound in the presence of WSC [1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride] and HOBT (1-hydroxybenzotriazole hydrate) in dimethylformamide or tetrahydrofuran The amine compound of the formula: wherein Rg is selected from the group consisting of linear or branched C3-8 alkyl, C1-3 alkyl substituted by at least one fluorine atom, cyclopentyl, cycloheptyl and cyclohexylmethyl, can be obtained according to J. Med. Chem. , 42, 2879 (1999). 22 The compound (I), wherein L has a part aikyl ketone at its terminal, or the compound (11-3) wherein A is C 1-5 alkyl, can be obtained by reacting the compound (V) described above with the compound ( VIII): Ph3P = CHCO-R7 (VIII) wherein, R7 is C1-5 alkyl. The compound (VIII) can be obtained according to Synthesis, 1055 (1987). The compound (I), where L is - (CH2) n-H can be obtained according to the scheme shown below using the compound (IV) as the starting material.
(IV-a) (IV-b) (IV-c) [wherein R-i and R2 are as defined above, R5 is alkyl]. The compound (IV) is reacted with a Grignard reagent of R6-MgBr (where R6 is alkyl) to give the compound (IV-a), and further reacted in the presence of triethylsilane and trifluoroacetic acid in dichloromethane to give the compound (IV-b) and then, is reduced with palladium on carbon catalyst to give the compound (IV-c). The compound (I), where L is: (CH2) n'- T- G 23 wherein T, G and n 'are as defined above with the exception that G is not hydrogen or alkylcarbonyl, can be prepared by reacting the compound (VII) with an alcohol, tyl or amine represented by: GTH (wherein G and T are as defined above, with the exception that G is not hydrogen or alkylcarbonyl). (1) The compound wherein T is oxygen or sulfur, or the compound shown below: wherein Ri and F¾ are as defined above, T is oxygen or sulfur, G is linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine or 2-methoxyethyl, n 'is an integer of 1-3, can be obtained by reacting the compound (VII) with correspog alcoholate or thiolate by heating. The alcoholate or thiolate can be prepared from the correspog alcohol or thiol and metallic sodium. (2) The compound wherein T is NH or the compound shown below: 24 wherein Ri, R2 and n 'are as defined above, G is lower alkyl, can be obtained by the compound (VII) with the correspog amine. The compound of formula (I) wherein L is: wherein T is oxygen and G is alkylcarbonyl, or the compound shown below: wherein Ri, R2 and n 'are as defined above, R9 is lower alkyl, can be obtained by reacting the compound (VI) with an acid chloride compound of: CI-CO-R9, wherein R9 is as defined higher. The compound of formula (I) wherein L is: 25 wherein n 'and R3 are as defined above, for example, the compound shown below: wherein R-i, R2 and R3 are as defined above, can be prepared by reacting the compound of formula (IX): (IX) wherein R3 is as defined above with the compound (VII) in the presence of triethylamine.
Compound of formula (I) wherein X is sulfur or the compound shown below: wherein R-i, R2 and L are as defined above can be obtained by reacting a compound of: wherein Ri, f¾ and L are as defined above, with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphenytane-2,4-disulfide (Lawesson's reagent) in toluene , warming up. The compound of formula (I), wherein L is: wherein 3 is as defined above, can be obtained by reacting the compound (V) with the compound: wherein R3 is as defined above, according to Japanese published patent application No. 47-12322. 27 . The compound of formula (I), wherein L is: Where f¾ and E are as defined above, it can be obtained by reacting the compound (V) with sodium hydride and then reacting with ethyl bromoacetate to give the compound (X), and then hydrolyzing the compound (X) with an alkali to give the carboxylic acid compound (11-1 d) and followed by esterification or amidation.
(X) (IHd) The compound of formula (I), wherein L is: 28 where R3 is as defined above, = CH-C-OE II O Wherein It is as defined above, it can be obtained by converting the compound (III) to the compound (XI) indicated below in accordance with Aust. J. Chem., 35, 2077 (1982), and reacting the compound with an amine of: R2-NH2 (wherein R2 is as defined above) by heating to give the compound (XII). The compound is then hydrolyzed with an alkali and then esterified or amidated to give the desired compound.
The compounds of formula (I), wherein the L-terminus is a carboxyl group, such as that of (11-1), can be provided as a metal salt with sodium, potassium or calcium. When the compound of formula (I) is basic, the compound can be provided as an acid addition salt, especially the pharmaceutically acceptable salt with an acid. Examples of the salt may include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate and hydrobromide and organic salts such as acetate, propionate, fumarate, maleate, tartrate, citrate, malate, oxalate, benzoate, methanesulfonate and benzenesulfonate. The compound of the invention can have optical isomers and the scope of the invention covers both optical isomers and the racemic compound. Generally, the compound of the present invention is obtained as racemic and can be divided into the optical isomers in a conventional manner known in the art. The compound of the invention is useful for anesthesia by inducing sedation in the mammal. The three components of anesthesia are sedation (unconsciousness), analgesia (blocking the reception and transmission of the sensation of pain) and muscle relaxation (blocking of unwanted body movement or dangerous reflex response). After clinical anesthesia, the compounds having respective activities are used in combination in anesthesia, as required. The isoindoline derivatives of the present invention have excellent sedative properties on mammals such as humans and are therefore effectively used as an anesthetic for mammals. The compound of the present invention has a wider safety margin than commercially available intravenous anesthetics such as propofol or thiopental sodium as well as rapid introduction and recovery of anesthesia. 30 The compound of the present invention can be easily prepared by being water soluble or water miscible to form a pharmaceutically acceptable salt thereof, or by preparing a solution with a solubilizer. Accordingly, the compound of the present invention is useful for the preparation of an ideal intravenous anesthetic composition. Examples of pharmaceutically acceptable salts may include those mentioned above. The anesthetic composition of the present invention can be formulated to be administered orally or parenterally, such as intravenously, epidurally, spinally, subcutaneously or intramuscularly to a mammal such as a human. Examples of the dosage form of the composition may include tablets, granules, capsules, solution for injection, ophthalmic solution, eye ointment and suppositories. Preferably, the composition of the invention is an intravenous anesthetic composition prepared by dissolving the compound with or without a solubilizer in a pharmaceutically acceptable carrier. Examples of the pharmaceutically acceptable carriers used in the composition of the present invention may include purified water, saline, solvent for injection and Ringer's solution, with saline being preferred. Most pharmaceutically acceptable salts of compound (I) are soluble in water and some water-insoluble compounds.
They can be dissolved in water with a solubilizer. Examples of solubilizers may include cyclodextrin, glycerin, ethanol, propylene glycol and polyethylene glycol. The anesthetic composition of the invention can be formulated as a powder composition to be dissolved in an appropriate vehicle such as water or saline prior to use. The anesthetic composition of the invention may further comprise other ingredients, which are used in a conventional anesthetic composition. The other ingredients may include, but are not limited to, an isotonic agent such as sodium chloride and glucose; pH regulating agent such as calcium citrate, sodium citrate, potassium acetate, sodium acetate, sodium hydrogen phosphate and potassium dihydrogen phosphate; antiseptics such as benzyl alcohol and phenol; antioxidants such as sodium pyrosulfite, sodium hydrogen sulfite and ascorbic acid; preservatives such as benzethonium chloride, benzalkonium chloride, phenol, cresol, chlorobutanol and benzyl alcohol; and chelating reagents such as EDTA, thioglycolic acid, thiolactic acid and thioglycerin. The anesthetic composition of the invention may contain other pharmacologically active ingredients, as long as they are not contrary to the objects of the present invention. The anesthetic composition of the invention can be administered intravenously to induce general anesthesia. The composition is effective for the induction and maintenance of the anesthesia state in a surgical operation as well as for the control of postoperative sedation and for the control of sedation in a ventilated patient undergoing intensive treatment. The anesthetic composition of the invention can be used at any stage of anesthesia in combination with a suitable analgesic and / or muscle relaxant, if desired. The effective anesthetic amount of the compound (I) or a salt thereof is not limited and may vary depending on the age, sex, body weight and physical condition of the patient to be treated, the desired depth or the retention time of the patient. anesthesia and the like. For the induction of anesthesia, they are typically administered approx. 0.1-10 mg / kg, preferably 1.0-5.0 mg / kg bolus of the compound of the present invention intravenously. For maintenance, 0.5-25 mg / kg / hour, preferably 1.0-15 mg / kg / hour of the compound are intravenously administered continuously. To maintain sedation in a patient who is going to be subjected to intensive treatment or for postoperative sedation, 0.05-10 mg / kg / hour, preferably 0.1-5.0 mg / kg / hour of the composition are administered intravenously. These amounts are only examples and do not limit the scope of the invention. The present invention will be further illustrated by means of the following test examples, reference examples and examples; however, the present invention is not limited by those examples. 33 REFERENCE EXAMPLE 1 4,5-Diethylphthalic Anhydride (a) 4,5-diethylphthalic acid 1,2-dicyano-4,5-diethylbenzene (2.3 g, 12 mmol) was stirred with heating in 75% sulfuric acid (30 ml) at 150 ° C for 3.5 h. The reaction solution was poured into ice water. The precipitated crystals were collected by filtration, washed with water and dissolved in 10% aqueous sodium hydroxide solution. Insoluble materials were separated by filtration and the resulting filtrate was acidified with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to give 1.5 g of 4,5-diethylphthalic acid. (b) 4,5-diethylphthalic anhydride The product mentioned above (a) (1.5 g, 6.7 mmol) was heated under reflux in acetic anhydride (10 ml) for 1 h. The reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in 10% aqueous sodium hydroxide solution. The insoluble materials were collected by filtration, washed with water and dried to give 0.31 g of the title compound. 3. 4 REFERENCE EXAMPLE 2 3,5-dimethylphthalic anhydride 4,6-Dimitel-2-pyrone (1.0 g 8.1 mmol) and 2-chloromaleic anhydride (1.5 g, 11 mmol) were stirred with heating at 160 ° C for 3 hr, and the precipitated crystals were purified by gel chromatography. silica (chloroform) to give 0.91 g of the title compound.
REFERENCE EXAMPLE 3 4,5-dimethylphthalic anhydride (a) 5.6-dimethyl-3a-4,7,7a-tetrahydro-2-benzofuran-1,3-dione To a solution of maleic anhydride (5.4 g, 55 mmol) in benzene (50 ml) was added dropwise. , 3-dimethyl-1,3-butadiene (6.3 ml, 55 mmol) and stirred overnight at 25 ° C. After separating the insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give 9.5 g of 5,6-dimethyl-3a, 4,7,7a-tetrahydro-2-benzofuran-1,3-dione. (b) 4,5-dimethylphthalic anhydride To a solution of (a) above (9.5 g, 53 mmol) in acetic acid (28 ml), a solution of bromine (6.1 ml, 0.12 mmol) in acid was added dropwise. acetic acid (28 ml) at 115 ° C over a period of 45 35 minutes and heated to reflux for 1 h. The reaction solution was left overnight and the precipitated crystals were collected by filtration, washed with diethyl ether followed by drying to give 3.5 g of the title compound.
REFERENCE EXAMPLE 4 4,5-Dimethoxyphthalic Anhydride (a) 4,5-dimethoxy-fatale 3,4-dimethoxybenzoic acid (5.0 g, 27 mmol) was added to formalin (36 ml) saturated with hydrogen chloride gas, and stirred with bubbling hydrogen chloride gas at 65 ° C. C for 2 hs. The reaction solution was concentrated under reduced pressure and water was added to the residue (16 ml), followed by neutralization with dilute aqueous ammonia (concentrated aqueous ammonia: water = 2: 3.) The precipitated crystals were collected by filtration, washed with water , followed by drying to give 4.0 g of 4,5-dimethoxy-fatale. (b) 4,5-Dimethoxyphthalic Acid A solution of aqueous sodium hydroxide was added dropwise 2N of the above-mentioned product (a) (3.0 g, 15 mmol) with stirring to a 6% aqueous solution of potassium permanganate (50 ml) under cooling with ice, and the reaction solution was stirred overnight increasing 36 gradually the temperature at 25 ° C. Ethanol was added to the reaction solution and the precipitated manganese dioxide was filtered. The filtrate was acidified with concentrated hydrochloric acid under reduced pressure. Methanol was added to the residue and stirred for 10 minutes. After filtering the insoluble materials the filtrate was concentrated under reduced pressure to give 4.1 g of 4,5-dimethoxyphthalic acid. (c) 4,5-dimethoxyphthalic anhydride The product (b) mentioned above (4.1 g, 18 mmol) was heated to reflux in acetic anhydride (14 ml) for 10 minutes. The reaction solution was poured into ice water, and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then water, dried and concentrated under reduced pressure to give 1.8 g of the title compound.
REFERENCE EXAMPLE 5 5,6-indanedicarboxylic anhydride (a) diethyl ester of 5,6-indanedicarboxylic acid Acetyldicarboxylic acid diethyl ester (1.0 ml, 6.3 mmol) and dicarbonylcyclopentadienylcobalt (0.1 ml, 0.62 mmol) were added dropwise to a solution of 6-heptadiin (0.72 ml, 6.3 mmole) in xylene (5 ml), and stirred at 80 ° C for 5 days. To the reaction solution is 37 He added dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, followed by purification of the residue by silica gel chromatography (chloroform, successively hexane: ethyl acetate = 10: 1) to give 0.36 g of diethyl ester of 5,6-indanedicarboxylic acid. (b) 5,6-Indanedicarboxylic acid To a solution of the above-mentioned product (a) (0.36 g, .4 mmol) in acetic acid (0.8 ml) was added concentrated hydrochloric acid (0.4 ml) and stirred at 80 ° C. overnight. Ice water was added to the reaction solution and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.28 g of 5,6-indanedicarboxylic acid. (c) 5,6-indanedicarboxylic anhydride The product (b) mentioned above (0.28 g, 1.4 mmol) was heated under reflux in acetic anhydride (6.7 ml) overnight. The reaction solution was poured into ice water and the precipitated crystals were collected by filtration, washed with water followed by drying to give 0.25 g of the title compound. 38 REFERENCE EXAMPLE 6 5,6,7,8-Tetrahydro-2,3-naphthalenedicarboxylic acid anhydride Using 1, 7-octadiin as the starting material, the title compound was obtained according to reference example 5.
REFERENCE EXAMPLE 7 1,3-Dihydro-2-benzofuran-5,6-dicarboxylic acid anhydride Using propargyl ether as the starting material, the title compound was obtained according to reference example 5.
REFERENCE EXAMPLE 8 1,3-Benzodioxol-5,6-dicarboxylic acid anhydride Using 1,2-dibromo-4,5- (methylenedioxy) benzene, the title compound was obtained according to the synthesis of 4,5-diethylphthalic anhydride. 39 EXAMPLE 1 5.6-DimetH-2- (4-fluorophenyl) -3-carboxymethylisoindolin-1-one [IUPAC Name: 2-r2- (4-fluorophenyl) -5,6-dimethyl-3-oxo-2,3- acid dihydro-1 H-isoindol-1-lactic acid (1-a) 5,6-Dimethyl-2- (4-fluorophenyl) isoindolyl-1,3-dione 4.5-Dimethylphthalic anhydride (1.7g, 9.6mmol) and 4-fluoraniline (1) were stirred. , 1 g, 9.6 mmol) with heating in dimethylformamide at 150 ° C for 1 h. After cooling, water was added to the reaction mixture and the precipitated crystals were collected by filtration, washed with water and dried. The resulting crystals were purified by chromatography on silica gel (chloroform) to give 2.0 g of 5,6-dimethyl-2- (4-fluorophenyl) isoindolyl-1,3-dione. 1 H-NMR (CDCl 3) 5: 2.44 (6H, s, CH 3), 7.15-7.22 (2H, m, PhH), 7.38-7.45 (2H, m, PhH), 7.71 (2H, s, C4.7-H ); (1-b) 5.6-dimethyl-2- (4-fluorophenyl) -3-hydroxyisoindolin-1 -one The product of (1-a) mentioned above (1.0 g, 3.7 mmol) in methanol (9 ml) was suspended. ) and tetrahydrofuran (9 ml), and sodium borohydride (0.15 g, 3.9 mmol) was added in portions thereto with stirring under ice-cooling, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution and collected for 40 minutes.
Filtration the precipitated crystals, washed with water, followed by drying to give 0.95 g of 5,6-dimethyl-2- (4-fluorophenyl) -3-hydroxyisoindolin-1-one. (1-c) 5,6-dimethyl-2- (4-fluorophenyl) -3-ethoxycarbonyl-methylisoindolyl-1-one [IUPAC designation: ethyl 2-r2- (4-fluoropheni-5,6- dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yleacetatol The product of (1-b) mentioned above (0.90 g, 3.3 mmol) and (carboethoxymethylene) triphenylphosphorane (1.4 g, 3.9 mmoles) was heated under reflux in toluene (15 ml) under an argon atmosphere for 3.5 hrs The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: methanol = 50: 1) to give 0.37 g of 5,6-dimethyl-2- (4-fluorophenyl) -3-ethoxycarbonylmethyl isoindolyl-1-one [IUPAC designation: ethyl 2- [2- (4-fluorophenyl) -5, 6-dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl-cacetate]. 1 H-NMR (CDCl 3) d: 1.18 (3 H, t, CH 2 CH 3), 2.36 (3 H, s, CH 3), 2.38 (3H, s, CH3), 2.50 (1 H, dd, CH2), 2.85 (1 H, dd, CH2), 4.02-4.15 (2H, m, CH2CH3), 5.46 (1 H, dd, CH), 7.10 -7.18 (2H, m PhH), 7.27 (1 H, s, C7-H), 7.48-7.54 (2H, m, PhH), 7.68 (1 H, s, C4-H). 41 (1-d) 5,6-dimethyl-2- (4-fluorophenyl) -3-carboxymethylisoindolin-1 -one [IUPAC designation: 2-f2- (4-fluororenyl-V-5,6-dimethyl-3-oxo-2, 3-dihydro-1 H-isoindol-1-ylacycloeticol The product of (1-c) mentioned above (0.20 g, 0.59 mmol) was stirred with heating in methanol (1.5 ml) and 15% aqueous carbonate solution. potassium (0.46 ml) at 75 ° C for 4 hrs. The reaction solution was concentrated under reduced pressure and water was added to the residue followed by extraction with diethyl ether.The water layer was acidified with concentrated hydrochloric acid and the crystals were collected precipitated by filtration, washed with water, followed by drying to give 0.12 g of the title compound.1H-NMR (DMSO-de) d: 2.32 (3H, s, CH3), 2.34 (3H, s, CH3) 2.52 (1 H, dd, CH2), 2.80 (1H, dd, CH2), 5.55 (1 H, dd, CH), 7.26-7.30 (2H, m, PhH), 7.44 (1 H, s, CT-H) , 7.54 (1H, s, C -H), 7.57-7.61 (2H, m, PhH).
EXAMPLE 2 Using isoindoline-1,3-dione 5,6-dimethyl-2-substituted as starting material isoindolin-1-one 5,6-dimethyl-3-carboxymethyl-2-substituted was obtained according to example 1. 42 EXAMPLE 3 5,6-dimethyl-2- (3-fluorophenyl) -3- (4-metH-1-plperazinyl) carbonylmethylisoindolin-1 -one 5,6-dimethyl-2- (3-fluorophenyl) -3-carboxymethylsoindolin-1-one [IUPAC name: 2- [2- (4-fluorophenyl) -5,6-dimethyl-oxo-2] , 3-dihydro-1 H-isoindol-1-yl] acetic acid] (0.50 g, 1.6 mmol), 1-methylpiperazine (0.16 g, 1.6 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 0.31 g, 1.6 mmol), and 1-hydroxybenzotriazole hydrate (0.25 g, 1.6 mmol) were stirred in tetrahydrodurane (40 ml) at 25 ° C for 16 h. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: methanol = 20: 1) to give 0.56 g of the title compound. 1 H-NMR (CDCl 3) d: 2.16-2.26 (2 H, m, piperazine), 2.27 (3 H, s, NHC 3), 2.36 (3 H, s, CH 3), 2.37 (3 H, s, CH 3), 2.34-2.42 ( 2H, m, piperazine), 2.41 (1 H, dd, CH2), 2.91 (1 H, dd, CH2), 3.20-3.31 (2H, m, piperazine), 3.64-3.72 (2H, m, piperazine), 5.77 (1 H, dd, CH), 6.88-6.93 (1 H, m, PhH), 7.38 (1 H, s, C4-H), 7.35-7.42 (2H, m, PhH), 7.58-7.62 (1 H , m, PhH), 7.68 (1 H, s, C7-H). 43 EXAMPLE 4 5,6-dimethyl-2- (4-fluorophenin-3-carboxymethylisoindolin-1-one [IUPAC name: 3-r 2 - (4-fluorophenyl) -5,6-dimethyl-3-oxo-2,3 acid - dihydro-1 H-isoindol-1-methylpropionicol (4-a) 5,6-dimethyl-2- (4-fluorophenyl) -3- (2-hydroxyethanol-isoindolin-1-one) To a solution of lithium borohydride (80 mg, 3.7 mmol) in tetrahydrofuran was added with stirring 5,6-dimethyl-2- (4-fluorophenyl) -3-ethoxycarbonylmethylisoindolin-1-one [IUPAC Designation: ethyl 2- [2- (4-fluorophenyl) -5, 6-dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl] acetate] (0.63 g, 1.9 mmol) under ice-cooling and stirred at 25 ° C for 39 h. the reaction solution and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.51 g of 5,6-dimethyl-2- (4-florophenyl) -3- (2-hydroxyethyl) isoindoline-1 - ona H-NMR (CDCl3) d: 2.01 -2.25 (2H, m, CH2CH20), 2.37 (3H, s, CH3), 2.40 (3H, s, CH3), 3.50 (2H, dd, CH2CH20), 5.28 (1 H, dd, CH), 7.12-7.16 (1 H, m, PhH), 7.32 (1H, s, C4 -H), 7.52-7.55 (2H,, m PhH), 7.68 (1 H, s, C7-H). (4-b) 5.6-dimethyl-2- (4-fluorophenin-3-mesyloxyethyl isoindolin-1-one) To a solution of the product mentioned above (4-a) (0.20 g, 0.67 mmol) and triethylamine (0.14 ml, 1.0 mmoles) in dichloromethane was added mesyl chloride (0.06 ml, 0.78 mmol) and stirred at 25 ° C for 30 minutes, the reaction solution was washed with water, dried and the distillate was distilled. solvent under reduced pressure to give 0.23 g of 5,6-dimethyl-2- (4-fluorophenyl) -3-mesyloxyethyl-isoindolin-1 -one. 1 H-NMR (CDCl 3) d: 2.26-2.45 (2 H, m, CH 2 CH 20), 2.38 (3 H, s, CH 3), 2.41 (3 H, s, CH 3), 2.79 (3 H, s, CH 3 S0 2), 3.90-4.04 ( 2H, m, CH2CH20), 5.29 (1H, dd, CH), 7.14-7.18 (2H, m, PhH), 7.31 (1H, s, C4-H), 7.51-7-54 (2H, m, PhH) 7.70 (1 H, s, C7-H). (4-c) 5,6-dimethyl-2- (4-fluorophenyl) -3-cyanoethylisoindolyl-1-one r IUPAC denomination: 3-r2- (4-fluorophenyl) -5,6-dimethyl-3-oxo-2.3 -hydro-1 H-isoindol-1-illpropanonitrilol To a solution of 80% ethanol of the above-mentioned product (4-b) (0.23 g, 0.63 mmol) was added potassium cyanide (0.12 g, 1.9 mmol) and it was heated under reflux for 4 h. Water was added to the reaction solution and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off under reduced pressure to give 0.19 g of 5,6-dimethyl-2- (4-fluorophenol) -3-cyanoethylisoindolin-1-one [IUPAC Designation] : 3- [2- (4-fluororenyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl] propanenitrile]. 1 H-NMR (CDCl 3) 6: 1.77-1.99 (2H, m, CH 2 CH 20), 2.28-2.41 (2H, m, CH 2 CH 2 CN), 2.38 (3 H, s, CH 3), 2.42 (3 H, s, CH 3), 5.29 ( H, dd, CH), 7.15-7.20 (2H, m, PhH), 7.26 (1 H, s, C7-H), 7.50-7.53 (2H, m, PhH), 7.70 (1 H, s, C4- H).
Four. Five (4-d) 5,6-dimethyl-2- (4-fluorophenin-3-carboxyethyl-isolndol-1-one [IUPAC name: 3- [2- (4-fluorophenyl) -5] , 6-dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-methylpropionic The above-mentioned product (4-C) (0.18 g, 0.58 mmol) was heated under reflux in concentrated hydrochloric acid (10 ml). ) overnight, water was added to the reaction solution and the precipitated crystals were collected by filtration, washed with water, and dried to give 0.15 g of the title compound.
EXAMPLE 5 5,6-Diml-2- (4-fluoropheni-3- (4-ml-1-piperazine-P-carbonyll isoindolin-1-one) Using 5,6-diml-2- (4-fluorophenyl) -3-carboxylisoindolin-1-one [IUPAC name: 3- [2- (4-fluorophenyl) -5,6-diml-3-oxo- 2,3-dihydro-1H-isondol-1-yl] propionic acid] the title compound was obtained according to example 3. 1 H-NMR (CDCl 3) 5: 1.64-1.98 (2H, m, CH 2 CH 2 C = 0), 2.10-2.21 (2H, m, piperazine), 2.24 (3H, s, NCH3), 2.24-2.27 (2H, m), piperazine), 2.27-2.37 (2H, m, CH2CH2C = 0), 2.37 (3H, s , CH3), 2.39 (3H, s, CH3), 3.04-3.07 (2H, m, piperazine), 3.41-3.56 (2H, m, piperazine), 5.32 (1 H, dd, CH), 7.12-7.16 (2H , m, PhH), 7.26 (1 H, s, C4-H), 7.55-7.58 (2H, m, PhH), 7.68 (1 H, s, C7H). 46 EXAMPLE 6 The compounds shown in Tables 1 and 2, obtained in a manner similar to those described in Examples 3 and 5. 47 TABLE 1 48 The NMR data of each compound in Table 1 are shown below: No. 1: 1 H-NMR (CDCl 3) d: 2.17-2.25 (2 H, m, piperazine), 2.27 (3 H, s, NCH 3), 2.34-2.40 (2H, m, piperazine), 2.47 (3H, s, CH3), 2.83 (1 H, dd, CH2), 3.18-3.33 (2H, m, piperazine), 3.58-3.76 (2H, m, piperazine), 5.78 (1 H, dd, CH), 7.10-7.18 (2H, m, PhH), 7.33 (1 H, br d, C6-H), 7.41 (1 H, br s, C4-H), 7.56-7.63 ( 2H, m, PhH), 7.79 (1 H, d, C7-H). No. 2: 1 H-NMR (CDCl 3) d: 1.92-2.23 (4H, m, piperazine), 2.22 (3H, s, NCH3), 2.33 (3H, s CH3), 2.39 (3H, s, CH3), 2.64 (1 H, dd, CH2), 2.82 (1 H, dd, CH2), 3.03-3.25 (2H, m, piperazine ), 3.50-3.58 (2H, m, piperazine), 6.02 (1 H, dd, CH), 6.87-6.91 (1H, m, PhH), 7.30-7.46 (3H, m, PhH and C6-H), 7.60 -7.66 (2H, m, PhH and C7-H). No. 3: H-NMR (CDCl 3) d: 2.01-2.33 (4H, m, piperazine), 2.23 (3H, s, NCH3), 2.39 (3H, s, CH3), 2.43 (3H, s, CH3), 2.65 (1 H, dd, CH 2), 2.82 (1 H, dd, CH 2), 3.07-3.27 (2 H, m, piperazine), 3.49-3.60 (2 H, m, piperazine), 5.98 (1 H, dd, CH ), 6.87-6.92 (1 H, m, PhH), 7.22 (1 H, s, C5-H), 7.34-7.45 (2H, m, PhH), 7.56 (H, s, C7-H), 7.62- 7.66 (1 H, m, PhH). No. 4: 1 H-NMR (CDCl 3) d: 1.98-2.05 (1 H, m, piperazine), 2.16-2.35 (3 H, m, piperazine), 2.22 (3 H, s, NCH 3), 2.39 (3 H, s, CH3), 2.63 (1 H, dd, CH2), 2.71 49 (3 H, s, NCH 3), 2.83 (1 H, dd, CH 2), 3.07-3.27 (2 H, m, piperazine), 3.46-3.60 (2 H, m, piperazine), 5.97 (1 H, dd, CH), 6.87-6.92 (1 H, m, PhH), 7.16 (1 H, d, Ce-H), 7.26 (1 H, d, C5-H), 7.33-7.45 (2H, m, PhH), 7.63-7.66 (1 H, m, PhH). No. 5: 1 H-NMR (CDCl 3) d: 2.20-2.25 (2H, m, piperazine), 2.27 (3H, s, NCH3), 2.37-2.41 (2H, m, piperazine), 2.42 (3H, s, CH3), 2.44 (1H, dd, CH2), 2. 71 (3 H, s, CH 3), 2.88 (1 H, dd, CH 2), 3.21-3.31 (2 H, m, piperazine), 3.64-3.76 (2 H, m, piperazine), 5.75 (1 H, dd, CH) , 6.88-6.92 (1 H, m, PhH), 7.07 (1 H, s, C6-H), 7.21 (1 H, d, C4-H), 7.34-7.41 (2H, m, PhH), 7.59- 7.62 (1 H, m, PhH). No. 6: 1 H-NMR (CDCl 3) d: 2.20-2.23 (2 H, m, piperazine), 2.26 (3 H, s, NCH 3), 2.36-2.38 (2 h, m, piperazine), 2.36 (3 H, s, CH 3 ), 2.41 (1 H, dd, CH2), 2. 72 (3 H, s, CH 3), 2.87 (1 H, dd, CH 2), 3.19-3.30 (2 H, m, piperazine), 3.63-3.72 (2 H, m, piperazine), 5.74 (1 H, dd, CH) , 6.89-6.94 (1 H, m, PhH), 7.31-7.42 (4H, m, PhH and C4.5-H), 7.57-7.61 (H, m, PhH). No. 7: 1 H-NMR (CDCl 3) d: 1.25 (3H, t, CH 2 CH 3), 1.29 (3H, t, CH 2 CH 3), 2.20-2.22 (2H, m, piperazine), 2.26 (3H, s, NCH 3), 2.35-2.37 (2H, m, piperazine), 2.43 (1 H, dd, CH2), 2.72-2.77 (4H, m, CH2CH3), 2.81 (1 H, dd, CH2), 3.19-3.31 (2H, m, piperazine), 3.60-3.74 (2H, m, piperazine), 5.77 (1 H, dd, CH), 7.11-7.15 (2H, m, PhH), 7.38 (1 H, br d, C4-H), 7.58- 7.61 (2H, m, PhH), 7.73 (1 H, s, C7-H). fifty No. 8: 1 H-NMR (CDCl 3) d: 2.22-2.41 (4 H, m, piperazine), 2.26 (3 H, s, NCH 3), 2.38 (1 H, dd, CH 2), 2.85 (1 H, dd, CH2), 3.24-3.34 (2H, m, piperazine), 3.65-3.73 (2H, m, piperazine), 3.95 (3H, s, OCH3), 3.97 (3H, s, OCH3), 5.71 (1H, dd, CH ), 7.12-7.16 (2H, m, PhH), 7.15 (1 H, s, C4-H), 7.36 (1H, s, C7-H), 7.56-7.60 (2H, m, PhH). 51 TABLE 2 52 53 54 TABLE 2 CONTEST) No. R2 L Melting point [° C] ~ t .o.) 37 ~ - CH 259.5-261.5 ('V- \ _ / CF 3, CH 2, Cp-N \ / N 3, (, sa .l A -c, lor. Hi.d.rat .o). t.o,) to) to) / ~~ \ 226.5 - ^ ^ - OCH3 2 ^ N \ / N-CH 3, (decomposed) (salt 1-hydrochloride) 43 -. 43 - ^ -? 150-151 - ^ J- 0CH3 CH¾_N_ N V_ / (salt 1-dorhydrate) ) ) 46 f- \ -i V-OCF, CH2C-N _ N-CH3 257-258.5 O 55 ) ) ) ) ) ) ) ) 56 TABLE 2 (CONT.) No. 2 Melting point [° C] 59 / ~? CH - N N-CH, 138-145 N or while) 61 148.5-149 CH, C- v / N - nC "H17 (salt 1 -hydrochloride) N 62" / ~~? > CHjC-N N White crystal N 74 // -N 174.5-176 CH, C- N N- () (salt 1-hydrochloride) 57 TABLE 2 (CONT.i R2 Melting point [° C] 75 White crystal to) 58 EXAMPLE 7 5,6-Dimethyl-3-carboxymethyl-2- (3-pyridyl) Isoindolin-1-one [IUPAC designation: 2-r 5,6-dimethyl-3-oxo-2- (3-pyridinin-2, 3-dihydro-1 H-isoindol-1-acetic acid! (7-a) 5,6-Dimethyl-2- (3-pyridinisoindole-1,3-dione) 4,5-dimethylphthalic anhydride (2.0 g, 11 mmoles) and 3- were heated under reflux. aminopyridine (1.0 g, 11 mmol) in acetic acid (30 ml) during 1. 5 hours After cooling water was added, the precipitated crystals were collected by filtration, washed with water, followed by drying to give 2.3 g of 5,6-dimethyl-2- (3-pyridyl) isoindoline-, 3-dione. H NMR (CDCl 3) d: 2.46 (6H, s, CH 3), 7.44 (1 H, dd, PyH), 7.73 (2H, s, C4.7-H), 7.83 (1 H, ddd, PyH), 8.62 (1 H, dd, PyH), 8.78 (H, d, PyH). (7-b) 5,6-dimethyl-3-hydroxy-2- (3-pyridinisoindorin-1-one) The above-mentioned product (7-a) (0.50 g, 2.0 mmol) was suspended in methane (10 g). mi) and tetrahydrofuran (10 ml) and sodium borohydride (75 mg, 2.0 mmol) was added in portions to the same by stirring under ice-cooling, followed by stirring at the same temperature for 30 minutes.Water was added to the reaction solution and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.40 g of 5,6-dimethyl-3-hydroxy-2- (3-pyridyl) isoindolin-1 -one. 59 (7-c) 5,6-dimethyl-3-ethoxycarbonylmethyl-2- (3-pyridin-isoindolin-1-one [IUPAC name: ethyl 2-r5,6-dimethyl-3-oxo-2- (3-pyridinin -2,3-dihydro-1 H-isoindol-1-lacetate T The product obtained in the above-mentioned (7-b) (0.40 g, 1.6 mmol) and (carboethoxymethylene) triphenylphosphorane (0.66 g, 1.9 mmol) was heated under reflux in toluene (10 ml) under an argon atmosphere for 4.0 hrs. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: acetone = 5: 1) to give 0.37 g of 5 g. , 6-dimethyl-3-ethoxycarbonylmethyl-2- (3-pyridyl) - soindolin-1-one [IUPAC name: ethyl 2- [5,6-dimethyl-3-oxo-2- (3-pyridinyl) -2, 3-dihydro-1 H-isoindol-1-yl] acetate]. 1 H-NMR (CDCl 3) d: 1.19 (3 H, t, CH 2 CH 3), 2.37 (3 H, s, CH 3), 2.39 (3 H, s, CH 3) , 2.54 (1 H, dd, CH2), 2.91 (1H, dd, CH2), 4.03-4.15 (2H, m, CH2CH3), 5.58 (1H, dd, CH), 7.30 (1 H, s, C7-H) ), 7.40 (1 H, dd, PyH), 7.69 (1 H, s, C4-H), 8.10 (1H, ddd, PyH), 8.48 (1H, d d, PyH), 8.79 (1H, d, PyH). (7-d) 5,6-dimethyl-3-carboxymethyl-2- (3-pyridyl) isoindolin-1-one r IUPAC nomination: 2-r5,6-dimethyl-3-oxo-2-f3-pyridinyl acid ) -2.3-dihydro-1 H-isoindol-1-alkyl acetic acid] The product obtained in the above-mentioned product (7-c) (0.20 g, 0.59 mmol) was stirred with heating in methanol (1.5 ml) and 15% aqueous potassium carbonate solution (0.46 ml) at 75 ° C for 4 h. The reaction solution was concentrated under reduced pressure and water was added at 60 ° C. residue followed by extraction with diethyl ether. The water layer was acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.12 g of the title compound. 1 H-NMR (CDCl 3) d: 2.34 (3 H, s, CH 3), 2.36 (3 H, s, CH 3), 2.61 (1 H, dd, CH2), 2.87 (1 H, dd, CH2), 5.69 (H, dd, CH), 7.49 (1 H, s, C7-H), 7.50 (1 H, dd, PyH), 7.58 (1H, s, C4-H), 8.02 (H, br dd, PyH), 8.44 (1H, br d, PyH), 8.84 (1 H, d, PyH), 12.31 (1 H, br s, COOH) ).
EXAMPLE 8 5.6-dimethyl-3-propoxycarbonylmethyl-2- (3-pyridin-indindolin-1 -one [UPAC Name: propyl 2-r5,6-dimethyl-3-oxo-2- (3-pyridinin-2.3- dihydrogen-1H-isoindol-1-iriacetate To a solution of 5,6-dimethyl-3-carboxymethyl-2- (3-pyridyl) isoindolin-1-one [IUPAC designation: 2- [5,6-dimethyl-3-oxo-2- (3-pyridinyl ) -2,3-dihydro-1 H-isoindol-1-yl] acetic acid] (74 mg, 0.25 mmol), n-propyl alcohol (16 mg, 0.27 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) in dichloromethane was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (53 mg, 0.27 mmol) at 5 ° C and the temperature was raised to 25 ° C over a period of 1.5 h. The reaction solution was concentrated under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, successively water, dried, and concentrated under reduced pressure to give 34 mg of the title compound. 1 H-NMR (CDCl 3) d: 0.88 (3 H, t, CH 2 CH 2 CH 3), 1.58 (2 H, sextet, CH 2 CH 2 CH 3), 2.37 (3 H, s, CH 3), 2.39 (3 H, s, CH 3), 2.55 (1 H, dd , CH2), 2.93 (1 H, dd, CH2), 3.94-4.06 (2H, m, CH2CH2CH3), 5.58 (1 H, dd, CH), 7.30 (1H, s, C7-H), 7.40 (1 H , dd, PyH), 7.69 (1 H, s, C4-H), 8.10 (1 H, ddd, PyH), 8.48 (1 H, dd, PyH), 8.79 (1 H, d, PyH).
EXAMPLE 9 The compounds shown in table 3 were obtained according to example 8. 62 TABLE 3 10 CH2C-OCH2CH3 170-171.5 Nli,) 63 TABLE 3 (CONT.) 16 |OCH3 CI- ^ G OC ^ CHg 124-124.5 OR 18 -CHj CHrjC OCH CH 2II 2 3 White crystal or 19 H2CH2CHg White crystal 20 CH2C-OCH2CH2CF3 (-) > 140.5-143 N 21 (-) N 2II 2 2 129.5-133.5 or 22 CH2C-OCH (CH3) 2 141- 143 N O 23 · CH ^ C OC H2CH2CH2C Hg 116.5-117.5 = N O 27 \ ?? 20 - ??? 2 ?? (?? 3) 2 130-131 N O 64 TABLE 3 (CONT.) 65 TABLE 3 (CONT.) No. Melting point [° C] 43 (-) N 141-141.5 44 (-) '> CH2C 165.5-156 46 (-) "CH, C- CH, 162.5-163.5 48 CH.C - (-) 201.5-202 66 TABLE 3 (CONT.) O. Melting point [° C] 67 EXAMPLE 10 5,6-Dimethyl-3-hexyl-2- (3-pyridyl) isoindozol-1-one (10-a) 5,6-dimethyl-3-hexyl-3-hydroxy-2- (3-pyridiniso-indol-1-one) Magnesium metal (0.14 g, 5.6 mmol) and 1 g. -bromohexane (0.78 mL, 5.6 mmol) with heating at 65 ° C in anhydrous tetrahydrofuran (24 mL) under an argon atmosphere for 2 h, and 5,6-dimethyl-2- (3-pyridyl) isoindoline-1 was added, 3-dione (0.40 g, 1.6 mmol), followed by stirring at 25 ° C for 15 minutes, the reaction solution was poured into saturated aqueous NH 4 Cl solution and extracted with ethyl acetate.The organic layer was concentrated under reduced pressure. and the residue was purified by chromatography on silica gel (chloroform: acetone = 5: 1) to give 0.23 g of 5,6-dimethyl-3-hexyl-3-hydroxy-2- (3-pyridyl) isoindoline-1- ona.1H-NMR (CDCl3) d: 0.56-1.09 (8H, m, C ^ CHaCHaChbCl-bCHs), 0.73 (3H, t, CH2CH3), 1.85-2.07 (2H, m, CH2CH2CH2CH2CH2CH3), 2.27 (3H, s , CH3), 2.38 (3H, s, CH3), 5.20 (1 H, br s, OH), 7.22 (H, dd, PyH), 7.31 (1 H, s, C4-H), 7.34 (1 H, s, C7-H), 7.96 (1H, ddd, PyH), 8.29 (1 H, dd, PyH), 8.78 (1H, d, PyH), 8.78 (1H, d, PyH). 68 (10-b) 5,6-Dimethyl-3-hexylidene-2- (3-pyridyl) -isoindolin-1 -one The above-mentioned product (10-a) (0.23 g, 0.69 mmol) in a mixed solvent was added. methylene chloride (3.5 ml) and trifluoroacetic acid (1.4 ml) and triethylsilane (0.15 ml, 0.96 mmol) was added dropwise thereto, followed by stirring at 25 ° C for 2 h. The reaction solution was added in 1N aqueous K2C03 solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: acetone = 5: 1) to give 91 mg of 5,6-dimethyl-3-hexylidene-2- (3-pyridyl) isoindolin-1-one. 1 H-NMR (CDCl 3) d: 0.91 (3H, t, CH 2 CH 3), 1.32-1.61 (6H, m, CH2CH2CH2CH2CH3), 2.42 (3H, s, CH3), 2.47 (3H, s, CH3), 2.66 (2H, q, = CHCH2), 5.47 (1 H, t, = CHCH2), 7.70 (1 H, s, C4 -H), 7.73 (1 H, s, C7-H), 8.04 (1 H, dd, PyH), 8.48 (1 H, br d, PyH), 8.91 (1 H, br d, PyH), 9.00 ( H, br s, PyH). (10-c) 5.6-dimethyl-3-hexyl-2- (3-pyridyl) isoindolin-1-one To a solution of the above-mentioned product (10-b) (88 mg, 0.27 mmol) in ethanol (10 ml) was added 18 mg of 10% palladium on carbon and stirred vigorously under a hydrogen atmosphere at 25 ° C for 2 h. The reaction solution was filtered and the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: acetone = 5: 1) to give 20 mg of the title compound. H-NMR (CDCl 3) d: 0.77 (3H, t, CH 2 CH 3), 0.77-1.20 (8H, m, CH 2 CH 2 CH 2 CH 2 CH 2 CH 3), 1.85-2.02 (2H, m, CH 2 CH 2 CH 2 CH 2 CH 2 CH 3), 2.37 69 (3H, s, CH3), 2.41 (3H, s, CH3), 5.26 (1 H, dd, CH), 7.26 (H, s, C4-H), 7.39 (1H, dd, PyH), 7.68 (1 H, s, C7-H), 8.15 (1H, br dd, PyH), 8.45 (H, br d, PyH), 8.77 (1 H, br s, PyH).
EXAMPLE 11 5,6-dimethyl-2- (3-pyridyl) -3- (2-oxopentyl) isoindolin-1 -one They were heated under reflux in toluene (20 ml) 5,6-dimethyl-3-hydroxy-2- (3-pyridyl) isoindolin-1-one (0.30 g, 1.2 mmol) and 2-oxo-1-triphenylphosphoranylidene pentane ( 0.61 g, 1.8 mmol) under argon atmosphere for 20 h. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel ((chloroform: acetone-10: 1) to give 0.14 g of the title compound.1H-NMR (CDCl3) d: 0.88 (3H , t, CH2CH2CH3), 1.58 (2H, d, sextet, CH2CH2CH3), 2.33 (2H, t, CH2CH2CH3), 2.36 (6H, br s CH3), 2.61 (1H, dd, CH2), 2.99 (1 H, dd , CH3), 5.73 (1 H, dd, CH), 7.22 (1 H, dd, C4-H), 7.39 (1 H, dd, PyH), 7.68 (1 H, s, C7-H), 8.10 ( 1 H, ddd, PyH), 8.47 (1 H, br d, PyH), 8.78 (1 H, br s, PyH). 70 EXAMPLE 12 The compounds shown in table 4 were obtained according to examples 10 and 11, TABLE 4 No. R2 Melting point [° C1 idrato) 71 EXAMPLE 13 5,6-dirnethyl-2- (3-pyridyl-3-mesyloxyethyl isoindolin-1 -one (13-a) 5,6-Dimethyl-2- (3-pyridyl-V3- (2-hydroxyethyl-Viisoindolin-1-one) To a solution of 5,6-dimethyl-3-ethoxycarbonylmethyl-2- (3-pyridyl) isoindoline -1-ona [IUPAC Designation: ethyl 2- [5,6-dimethyl-3-oxo-2- (3-pyridinyl) -2,3-dihydro-1 H -isoindol-1-yl] acetate] ( 8.4 g, 26 mmol) in methanol (250 mL) was added in portions sodium borohydride (11 g, 0.52 mmol) and the reaction mixture was stirred with heating at 80 ° C for 3 h. A freeze, and the precipitated crystals were collected by filtration, washed with water and dried to give 5,6-dimethyl-2- (3-pyridiI) -3- (2-hydroxyhethyl) isoindolin-1-one H-NMR ( CDCl 3) d: 2.05-2.13 (1 H, m, CH 2 CH 2 OH), 2.22-2.30 (1 H, m, CH 2 CH 2 OH), 2.38 (3 H, s, CH 3), 2.41 (3 H, s, CH 3), 3.53 (2 H, t , CH2CH2OH), 5.42 (1 H, dd, CH), 7.35 (1H, s, C4-H), 7.40 (1H, dd, PyH), 7.70 (1H, s, C7-H), 8.16 (1H, ddd, PyH), 8.45 (1 H, dd, PyH), 8.81 (1H, d, PyH). (3-b) 5.6-dimethyI-2- (3-pyridyl) -3-mesyloxyethyl isoindolin-1 -one To a solution of the above-mentioned product (13-a) 5.5 g, 20 mmol) in methylene chloride (140 mL) triethylamine (5.4 mL, 29 mmol) and methanesulfonyl chloride (2.4 mL, 21 mmol) were added and stirred at 25 ° C for 2 h. The reaction solution was concentrated under reduced pressure and the purify the residue by chromatography on silica gel (chloroform: acetone = 20: 1) to give 5.5 g of the title compound. H-NMR (CDCl 3) d: 2.32-2.50 (2 H, m, CH 2 CH 20), 2.39 (3 H, s, CH 3), 2.42 (3 H, s, CH 3), 2.81 (3 H, s, CH 3 S0 2), 3.39-3.94 ( 1 H, m, CH2CH20), 4.03-4.09 (1 H, m, CH2CH20), 5.43 (1 H, dd, CH), 7.34 (1 H, s, C4-H), 7.42 (1 H, dd, PyH ), 7.71 (1 H, s, C7-H), 8.15 (1 H, br dd, PyH), 8.49 (1 H, br d, PyH), 8.82 (1 H, d, PyH).
EXAMPLE 14 5,6-Dimethyl-2- (3-pyridyl) -3- (2-propoxyethyl) isoindolin-1one Sodium metal (6.4 mg, 0.28 mmol) was stirred with heating in propanol (2 mL) at 110 ° C for 1 h and 5,6-dimethyl-2- (3-pyridyl) -3-mesyloxyethyl-isoindolin-1-one ( 50 mg, 0.14 mmol), followed by stirring with heating at 90 ° C for 3 h. Water was added to the reaction solution and extracted with chloroform. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: ethyl acetate = 1: 1) to give 12 mg of the title compound. H-NMR (CDCl 3) 6: 0.85 (3H, t, OCH 2 CH 2 CH 3), 1.50 (2H, sextet, OCH 2 CH 2 CH 3), 2.03-2.09 (1 H, m, CH 2 CH 30), 2.20-2.26 (1 H, m, CH 2 CH 20), 2.37 (3H, s, CH3), 2.40 (3H, s, CH3), 3.17-3.33 (4H, m, CH2CH2OCH2CH2CH3), 5.39 (1 H, dd, CH), 7.33 (1 H, s, C4-H) , 7.39 (1 H, dd, PyH), 7.69 (1 H, s, C7-H), 8.13 (H, ddd, PyH), 8.46 (1 H, dd, PyH), 8.84 (1 H, d, PyH ). 73 EXAMPLE 15 5,6-dimethyl-2- (3-pyridyl) -3 2- (propylamino) etinisoindolin-1 -one 5,6-Dimethyl-2- (3-pyridyl) -3-mesyioxy-ethyl-ishoisin-1-one (0.1 g) was stirred., 0.31 mmol) in n-propylamine (3 mL) at 25 ° C for 6 h. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: methanol = 15: 1) to give 85 mg of the title compound. H NMR (CDCl3) d: 0.81 (3H, t, NHCH2CH2CH3), 1.38 (2H, sextet, NHCH2CH2CH3), 2.07-2.33 (6H, m, CH2CH2NHCH2CH2CH3), 2.37 (3H, s, CH3), 2.40 (3H, s, CH3), 5.39 (1 H, dd, CH), 7.31 (1 H, s, C4-H), 7.39 (1 H, dd, PyH), 7.68 (1 H, s, C7-H), 8.14 (1 H, ddd, PyH), 8.44 (1 H, dd, PyH), 8.82 (1H, d, PyH).
EXAMPLE 6 5,6-dimethyl-2- (4-fluorophenyl) -3- (4-methyl-1-piperazinyl) -ethyl isoindolin-1-one A solution of 5,6-dιmethyl-2- (4-fluorophenyl) -3-mesyloxyethyl-isoindolin-1-one (0.27 g, 0.74 mmol), N-methylpiperazine (74 mg, 0.74 mmol) and triethylamine (74 mg, 0.74 mmol) in dichloromethane was stirred at 25 ° C for 60 h. The reaction solution was washed with water, dried and the solvent distilled off under reduced pressure. The residue was purified by chromatography on 74 silica gel (chloroform: methanol = 15: 1) to give 33 mg of the title compound. H-NMR (CD3OD) d: 1.93-2.34 (12H, m, piperazine and CH2CH2), 2.20 (3H, s, NCH3), 2.39 (3H, s, CH3), 2.43 (3H, s, CH3), 5.41 ( 1 H, dd, CH), 7.18-7.23 (2H, m, PhH), 7.42 (1 H, s, C4-H), 7.57-7.61, (2H, m, PyH), 7.59 (1 H, s, C7-H).
EXAMPLE 17 5,6-dimethyl-3-ethylcarbonyloxyethyl-2- (3-pyridyl) isoindolin-1 -one [IUPAC designation: ethyl 2-r 5,6-dimethyl-3-oxo-2- (3-p) ridinyl) -2,3-dihydro-1 H-isoindoM-m-propinatol A solution of 5,6-dimethyl-2- (3-pyridyl) -3- (2-hydroxyethyl) isoindolon-1-one (50 mg, 0.18 mmol), propionyl chloride (16 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in dichloromethane was stirred at 25 ° C for 3 hours. The reaction solution was washed with water, dried and the solvent distilled off under reduced pressure. The residue was purified by chromatography on silica gel (chloroform: methanol = 20: 1) to give 43 mg of the title compound. 1 H-NMR (CDCl 3) d: 1.00 (3H, t, CH 2 CH 3), 2.11 (2H, q, CH 2 CH 3), 2. 20-2.41 (2H, m, CH2CH20), 2.38 (3H, s, CH3), 2.41 (3H, s, CH3), 3.76-3.96 (2H, m, CH2CH3O), 5.37 (1H, dd, CH), 7.30, (1H, s, C7-H), 7.41 (1 H, dd, PyH), 75 7. 69 (1 H, s, C4-H), 8.18 (1 H, br d, PyH), 8.47 (1 H, br d, PyH), 8.79 (1 H, br s, PyH).
EXAMPLE 18 The compounds shown in table 5 were obtained according to examples 14, 15, 16 and 17. 76 TABLE 5 No. R2 Melting point [° C] CH2CH2OH 153-155 N > mouse CH2CH2OCH2CH3 157-176 > (Salt 1 -hydrochloride) N CH2CH2OCH2CH2CH3 121.5-123.5 10 N 5 CH2CH2OCH2CH2CH2CH3 95-97.5 > N 6 CH 2 CH 2 OCH (CH 3) 2 127-130 > N CH2CH2OCH2CH (CH3) 2 1 10-1 11.5 > N CH2CH2OCH2CH2OCH3 94-96 15 N CH2CH2CH2OCH2CH3 119-122 > N 10 CH2CH2CH2OCH2CH2CH3 108-111.5 eleven } C ^ CHzCHzOCHaCHzCHaCHs White crystal ) 15 CH2CH2OCH2CH CH3 138-140 77 EXAMPLE 19 5,6-DimetH-2-f4-fluorophenii) -3- (4-methy1-1-plperazinyl) carbonylmethylisoindolin-1-thione and 5,6-dimethyl-2- (4-fluorophenyl) - 3- (4-methyl) -1-piperazinyl) thiocarbonylmethyl-isoindolin-1-thione 5,6-Dimethyl-2- (4-fluorophenyl) -3- (4-methyl-1-p-piperazinyl) carbonylmethyl isoindolon-1-one (60 mg, 0.15 mmol) were heated under reflux. ) and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosptane-2,4-disulfide (67 mg, 0.17 mmol) in toluene (0.5 ml) under an argon atmosphere for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: methanol = 30: 1) to give 14 mg and 25 mg of the title compound, respectively. 5,6-dimethyl-2- (4-fluorophenyl) -3- (4-methyl-1-piperazinyl) -carbonylmethylisoindolin-1-thione H-NMR (CDCl 3) d: 2.16-2.42 (4H, m, piperazine), 2.27 (3H, s, NCH3), 2.37 (3H, s, CH3), 2.38 (3H, s, CH3), 2.48 (H, dd, CH2), 2.73 (1H, dd, CH2), 3.18-3.36 (2H, m, piperazine), 3.49-3.76 (2H, m, piperazine), 5.80 (1H, dd, CH), 7.14-7.24 (2H, m, PhH), 7.33 (1 H, s, C4-H), 7.47-7.56 (2H, m , PyH), 7.89 (1H, s, C7-H). 5,6-Dimethyl-2- (4-fluorophenyl) -3- (4-methyl-1-piperazinyl) -thiocarbonylmethylindoindo-1-thione H-NMR (CDCl 3) d: 2.09-2.60 (4H, m, piperazine ), 2.28 (3H, s, NCH3), 2.37 (3H, s, CH3), 2.38 (3H, s, CH3), 2.87 (1 H, dd, CH2), 3.08 (1 H, dd, 78 CH2), 3.39-3.55 (2H, m, piperazine), 4.15-4.61 (2H, m, piperazine), 6.31 (1 H, dd, CH) 7.15-7.24 (2H, m, PhH), 7.34 (1H, s, C4-H), 7.56-7.66 (2H, m, PyH), 7.90 (1 H, s, C7-H).
EXAMPLE 20 5,6-dimethyl-3-ethoxycarbonylmethyl-2- (3-pyridyl) isoindolin-1-thione r IUPAC designation: ethyl 2-r5.6-dimethyl-2-3-pyridinyl) -3-thioxo-2,3-dihydro - 1 H-isoindoI-1-iHacetatol 5,6-Dimethyl-3-ethoxycarbonylmethyl-2- (3-pyridyl) - soindolin-1-one were heated under reflux [IUPAC name: ethyl 2- [5,6-dimethyl-3-oxo-2- (3- pyridinyl) -2,3-dihydro-H-isoindol-1-yl] -acetate] (0.10 g, 0.31 mmol) and 2,4-bis (4-methoxyphenyl) -1, 3-dithia-2,4-diphosphtane -2,4-disulfide (69 mg, 0.17 mmol) in toluene (1.5 ml) under an argon atmosphere for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: acetone = 10: 1) to give 97 mg of the title compound. 1 H-NMR (CDC) d: 1.15 (3 H, t, CH 2 CH 3), 2.39 (6 H, br s, CH 3), 2.65 (1 H, dd, CH 2), 2.79 (1 H, dd CH 2), 3.98-4.05 ( 2H, m, CH2CH3), 5.63 (1 H, dd, CH), 7.28 (1 H, s, C7-H), 7.47 (1 H, dd, PyH), 7.91 (1 H, s, C4-H) , 7.97 (1 H, ddd, PyH), 8.65 (1 H, dd, PyH), 8.75 (1 H, d, PyH). 79 EXAMPLE 21 The compounds shown in table 6 were obtained according to examples 19 and 20.
TABLE 6 No. Melting point [° C]) ) 80 EXAMPLE 22 5,6-dimethyl-2-f4-fluorophenin-3-rfE) -2-f4-methyl-1-piperazinin-2-oxo-ethylideneolisoisole-1-one (22-a) 5,6-dimethyl-3-rivE-2-ethoxy-2-oxoethylidene-2- (4-fluorophenidiandolin-1-one r IUPAC designation: ethyl 2-r 2 - (4-fluorophenyl) -5.6 -dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene-1-acetate Ethyl (E) -5,6-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-ylidene acetate (0.20 g, 0.81 mmol) and 4-fluoroaniline (0.10 g, 0.89 mmol) were stirred with warming acetic acid at 110 ° C for 7 hs. The reaction solution was concentrated under reduced pressure and methanol was added to the residue. The resulting crystals were collected by filtration and dried to give 0.24 g of 5,6-dimethyl-3 - [(E) -2-ethoxy-2-oxoetylidene] -2- (4-fluorophenol) isoindolin-1-one [IUPAC name: ethyl 2- [2- (4-fluorophenyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene] acetate]. 1 H-NMR (CDCl 3) d 1.30 (3 H, t, CH 2 CH 3), 2.42 (3 H, s, CH 3), 2.46 (3 H, s, CH 3), 4.23 (2 H, q, CH 2 CH 3), 5.41 (1 H, s, CH), 7.21-7.30 (4H, m, PhH), 7.70 (1H, s, C7-H), 8.89 (H, s, C4-H). 81 (22-b) 5,6-dimethyl-3-r (E) -2-hydroxy-2-oxoethylidene-1-2-r4-fluoropheniOisoindolin-1-one [IUPAC designation: 2-f2- (4-fluorophen n-5,6-dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-ylidenolacrylic; 5,6-dimethyl-3 - [(E) -2-hydroxy-2-oxoetyl) Deno] -2- (4-fluorophenyl) isoindolin-1-one [IUPAC name: 2- [2- (4-fluorophenyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H- isoindo! -1-ylidene] acetic acid] from the above-mentioned product (22-a) according to (1-d) of example 1. 1 H-NMR (DMSO-d 6) d 2.40 (6H, s, CH 3 ), 5.23 (1H, s, CH), 7.40-7.49 (4H, m, PhH), 7.69 (1H, s, C7-H), 8.84 (1 H, s, C4-H) (22-c) 5.6-dimethyl-2- (4-fluorophenyl) -3-r (E) -2-f4-methyl-1-Diperazinin-2-oxo-ethylidene-isoindolyl-1-one The title compound was obtained from from the above-mentioned product (22-b) according to example 3. 1 H-NMR (CDCl 3) d 2.28-2.35 (2 H, m, piperazine), 2.30 (3 H, s, NHC3), 2.39 (3H, s, CH3), 2.40 (3H, s, CH3), 2.46-2.48 (2H, m, piperazine), 3.44-3.46 (2H, m, piperazine), 3.79-3.81 (2H, m , piperazine), 5.54 (1H, s, CH), 7.20-7.25 (2H, m, PhH), 7.31-7.36 (2H, m, PhH), 7.68 (1H, s, C7H), 7.89 (1H, s, C4-H). 82 EXAMPLE 23 The compounds shown in table 7 were obtained according to example 22.
TABLE 7 No. Melting point \ ° C \ 83 EXAMPLE 24 The compounds shown in table 8 were obtained according to examples 1 and 3.
TABLE 8 6 CH = CH-CH = CH CHjC-N N-CH, 203-205.5 84 EXAMPLE 25 5,6-Dimethyl-2- (3-fluorophenin-3-carboxyisoindolin-1-one [IUPAC Designation: 2- (3-fluorophenyl) -5,6-dimetM-3-oxo-1-isolndollnocarboxylic acid (25-a) methyl 4,5-dimetii-2-formylbenzoate To a solution of 4,5-dimethylphthalic anhydride (1.5 g, 8.5 mmol) in anhydrous tetrahydrofuran (25 ml) was added a solution of tri-tertiary hydride. butoxy aluminum 1.0 mol / l in anhydrous tetrahydrofuran (8.5 ml) with cooling under ice and argon atmosphere, and stirred for 1 h under cooling with ice. Ice water was added to the reaction solution and the insoluble materials were filtered. The filtrate was concentrated under reduced pressure to give, 6-dimethyl-3-hydroxyphthalide. To this was added methyl iodide (12 g, 85 mmol) and K2CO3 (9.4 g, 68 mmol) and heated under reflux in acetone solvent for 5 h. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform) to give 0.64 g of methyl 4,5-dimethyl-2-formylbenzoate. 1 H-NMR (CDCl 3) d 2.35 (6H, s, CH 3), 3.95 (3 H, s, CH 3), 7.72 (1 H, S, Ph H), 7.74 (1 H, s, Ph H), 10.59 (1 H, s, C (= 0) H). (25-b) 4,5-Dimethyl-2- (r (3-fluorophenyl) imino-methyl) benzoic acid methyl ester To a solution of the above-mentioned product (25-a) (0.64 g, 3.3 mmol) in absolute ethanol (16 ml) ) 3-fluoroaniline (0.37 g, 3.3 85) was added mmoles), and stirred at 25 ° C for 2 h. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform) to give 0.45 g of methyl 4,5-dimethyl-2-. { [(3-fluorophenyl) imino] meth} benzoate. 1 H-NMR (CDCl 3) d 2.35 (3 H, s, CH 3), 2.37 (3 H, s, CH 3), 3.93 (3 H, s, CH 3), 6.90-7.05 (3 H, m, Ph H), 7.31-7.36 (1 H, m, PhH), 7.78 (1 H, s, PhH), 8.00 (1 H, s, PhH), 9.20 (1 H, s, C (= N) H). (25-c) 5.6-dimethyl-2- (3-fluorophenin-3-cyanoisoindolin-1-one rDomination IUPAC: 2- (3-fluorophen-5,6-dimethyl-3-oxo-1-isoindolinecarbonitrilol The above-mentioned product (25-b) (0.45 g, 1.6 mmol), cyanotrimethylsilane (0.40 ml, 3.2 mmol) and aluminum chloride (13 mg) in anhydrous benzene (5.5 ml) at 25 ° C for 2 hrs were stirred Argon atmosphere The reaction solution was concentrated under reduced pressure and the residue was washed with petroleum ether to give 0.35 g of 5,6-dimethyl-2- (3-fluorophenyl) -3-cyanoisoindolin-1-one [Denomination] IUPAC: 2- (3-fluorophenyl) -5,6-dimethyl-3-γ-1-isoindoline-carbonitrile]. 1 H-NMR (CDCl 3) d: 2.41 (3H, s, CH 3), 2.44 (3H, s, CH3), 5.79 (1 H, s, CH), 6.96-7.02 (1 H, m, PhH), 7.40-7.47 (2H, m, PhH), 7.78 (1H, s, PhH), 7.65-7.70 (1H, s, PhH), 7.73 (1 H, s, PhH). 86 (25-d) 5,6-dimethyl-2- (3-fluorophenyl) -3-carboxyisoindolin-1-one Idignation lUPAC: 2- (3-fluorophenyl) -5,6-dimethyl-3-oxo-1-isoindolinecarboxylic acid The title compound (24 mg) was obtained from the above-mentioned product (25-c) (0.34 g, 1.2 mmole) according to (4-d) of example 4.
EXAMPLE 26 5,6-dimethyl-2- (3-fluorofenM) -3- (4-methyl-piperazinyl) -carbonyl-so-indolin-1-one Using 24 mg of 5,6-dimethyl-2- (3-fluorophenyl) -3-carboxyisoindolin-1-one [IUPAC name: 2- (3-fluorophenyl) -5,6-dimethyl-3-oxo-1- isoindolinecarboxylic acid], 10 mg of the title compound were obtained according to example 3. Melting point: 200-202 ° C. 1 H-NMR (CDCl 3) d: 2.00-2.38 (4H, m, piperazine), 2.20 (3H, s, NCH3), 2.37 (3H, s, CH3), 2.38 (3H, s, CH3), 3.15-3.75 ( 4H, br m, piperazine), 5.93 (1 H, s, CH), 6.85-6.91 (1 H, m, PhH), 7.27-7.43 (3H, m, PhH and C4-H), 7.69 (1 H, s, C7-H), 7.70-7.75 (1 H, m, PhH). 87 EXAMPLE 27 5,6-Dimethyl-2- (3-fluorophenyl) -3- (4-methyl-1-piperazine D-carbonyloxyisoindolin-1-one) A solution of 5,6-dimethyl-2- (3-fluorophenyl) -3-hydroxyisoindolin-1-one (83 mg, 0.31 mmol) in anhydrous dimethylformamide (3 mL) was added to a suspension of hydride. 65% sodium (13 mg, 0.34 mmol) in anhydrous dimethylformamide (3 mL) and stirred at 25 ° C for 35 minutes. Then, a solution of 1-chlorocarbonyl-4-methylpiperazine (50 mg, 0.31 mmol) in anhydrous dimethylformamide was added and stirred with heating at 70 ° C for 5 h. The reaction solution was concentrated under reduced pressure and water was added to the residue, followed by extraction with chloroform. The extract was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform: methanol = 20: 1). The resulting crystals were washed with petroleum ether to give 21 mg of the title compound. Melting point: 146-148 ° C. 1 H-NMR (CDCl 3) d: 2.38 (3 H, s, NCH 3), 2.40 (3 H, s, CH 3), 2.73 (3 H, s, CH 3), 3.01-3.14 (6 H, m, piperazine), 3.18-3.24 ( 1 H, m, piperazine), 3.32-3.38 (1H, m, piperazine), 6.43 (1H, s, CH), 6.85-6.91 (1 H, m, PhH), 7.33-7.39 (1H, m, PhH) , 7.36 (1 H, s, C4-H), 7.66 (1 H, s, C7-H), 7.66-7.76 (2H, m, PhH). 88 EXAMPLE 28 5,6-dimethyl-2-f3-fluorophenyl) -3-carboxymethyl-oxo-8-indindolin-1 -one n IUPAC designation: 2- acid. { r2- (3-fluorophenyl) -5,6-d-methyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl-oxo-acetic acid (28-a) 5,6-D -methyl-2- (3-fluorophenon-3-ethoxycarbonyl-methyloxyindolin-1-one) IUPAC designation: ethyl 2 - (["2- (3-fluorofeniiy-5,6 -dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1 -illoxijacetate] To a solution of 5, 6-dimethyl-2- (3-fluorophenyl) -3-hydroxyisoindole-1-one (0.15 g, 0.55 mmol) in anhydrous tetrahydrofuran (5 mL) was added 60% sodium hydride (24 mg, 0.60 mmol) and stirred on ice for 10 minutes. Then, ethyl bromoacetate (67 mL, 0.60 mmol) was added and stirred at 25 ° C overnight. The reaction solution was concentrated under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried and concentrated under reduced pressure to give 0.19 g of 5,6-dimethyl-2- (3-fluorophenyl) -3-ethoxycarbonylmethyloxyisoindolin-1-one [IUPAC designation: ethyl 2-. { [2- (3-fluorophenyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1 H -soindol-1-yl] oxy} acetate]. 1 H-NMR (CDCl 3) d 1.17 (3 H, t, CH 2 CH 3), 2.38 (3 H, s, CH 3), 2.40 (3 H, s, CH 3), 3.56 (1 H, dd, CH 2), 3.73 (1 H, dd, CH2), 4.05-4.11 (2H, m, CH2CH3), 6.52 (1 H, s, CH), 6.87-6.95 (1 H, m, PhH), 7.33-7.42 (1 H, m, PhH), 7.43 ( 1 H, s, C4-H), 7.63-7.82 (2H, m, PhH), 7.66 (1 H, s, C7-H). 89 (28-b) 5,6-dimethyl-2- (3-fluorophenyl) -3-carboxymethyloxy-isoindolin-1-one rDomination: iUPAC: 2 r2- (3-fluorophenin-5,6-dimethyl-3-oxo-2 acid, 3-dihydro-1 H-isoindol-1-yloxylacteicol The above-mentioned product (28-a) (0.19 g, 0.53 mmol) and 1 N NaOH were stirred with heating in methanol (5 ml) at 100 ° C. reaction solution under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate.The water layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate.The extract was washed with water, followed by NaCl saturated, dried and concentrated under reduced pressure to give 0.15 g of the title compound.
EXAMPLE 29 5.6-dimethyl-2-f3-fluorophenyl) -3-r2-f4-meth1l-1-piperazinyl) -2-oxoetiHisolindole-1 -one Using 0.15 g of 5,6-dimethyl-2- (3-fluorophenyl) -3-carboxymethyloxyisoindolin-1-one [IUPAC name: 2- acid. { [2- (3-fluorophenyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl] oxy} acetic], 0.16 g of the title compound was obtained according to example 3. Melting point: 196-197 ° C. H-NMR (CDCIs) d: 2.15-2.37 (4H, m, piperazine), 2.25 (3H, s, NCH3), 2.38 (3H, s, CH3), 2.40 (3H, s, CH3), 3.01-3.15 ( 2H, m, piperazine), 3.36-3.46 (1 H, m, piperazine), 3.54-3.64 (2H, m, piperazine and CH2), 3.80 (H, 90 dd, CH2), 6.58 (1 H, s, CH), 6.88-6.93 (1H, m, PhH), 7.35-7.41 (2H, m, PyH), 7.43 (1 H, s, C4-H), 7.63 -7.77 (2H, m, PhH), 7.67 (1 H, s, C7-C).
EXAMPLE 30 (+) - 5,6-dimethyl-3-propoxycarbonylmethyl-2- (3-pyridyl) -isoindolin-1-one [IUPAC name: propyl (H-2-r5,6-dimethyl-3-oxo -2- (3-pyridinyl-2,3-dihydro-1 H-isoindol--lacelacetate v-5,6-dimethyl-3-propoxycarbonylmethyl-2- (3-pyridyl) isoindolin-1-one r IUPAC nomination: propyl ( -) - 2-r5,6-dimethyl-3-oxo-2- (3-pyridinyl) -2,3-dihydro-1 H-isoindol-1-iHacetatol (30-a) (+) - 5,6-D -methyl-3-carboxymethyl-2- (3-pyridyl) -isoindolin-1-one rDomination IUPAC: (+) - 2-r5,6-dimethyl- 3-oxo-2- (3-pyridin-2,3-dihydro-1 H-isoindol-1-acrazol and (-) - 5,6-dimethyl-3-carboxymethyl-2- (3 -pyrene-isoindoline-1 -one [IUPAC name: (-) - 2-r5.6-dimethyl-3-oxo-2- (3-pyridinyl-2,3-dihydro-1 H-isoindole -1-lactic acid 5,6-Dimethyl-3-carboxymethyl-2- (3-pyridyl) isoindolin-1-one was reacted [IUPAC Name: 2- [5,6-dimethyl-3-oxo-2- ( 3-pyridinyl) -2,3-dihydro-1H-isoindol-1-ylcacetic acid] with (-) - phenylethylamine to form a salt, and the salt was subjected to fractional recrystallization using ethanol. with 1 N hydrochloric acid to give (+) - 5,6-dimethyl-3-carboxymethyl-2- (3-pyridyl) isoindolin-1-one [IUPAC name: (+) - 2- [5,6-dimethyl]] -3-oxo-2- (3-pyridinyl) -2,3-dihydro-1 H-butol-1-yl] acetic acid]. 91 Specific optical rotation [a]? = + 108.6 ° (c = 1.0, chloroform: methanol = 1: 1). Using (+) - phenylethylamine, (-) - 5,6-dimethyl-3-carboxymethyl-2- (3-pyridyl) isoindolin-1-one was obtained [IUPAC designation: (-) - 2- [5,6] -dimethyl-3-oxo-2- (3-pyridinyl) -2,3-dihydro-1 H-isoindol-1-yl] acetic acid] according to the above-mentioned method. Specific optical rotation [a] 29D = -106.4 ° (c = 1.0, chloroform: methanol = 1: 1). (30-b) (+) - 5,6-dimethyl-3-propoxycarbonylmethyl-2- (3-pyridyl) isoindolin-1-one r IUPAC designation: propyl V2-r5.6-dimethyl-3-oxo-3-f3 -pyridinin-2,3-di idro-1 H-isoindol--lacecetatol and (-) - 5,6-dimethyl-3-propoxycarbonylmethyl-2- (3-pyridyl) isoindolin-1-one [IUPAC name: propyl (-) - 2 -r5,6-dimethyl-3-oxo-2- (3-p iridin il 1-2, 3-d ih id ro- 1 H-isoindol-1-iHacetateT Using the above-mentioned isomer (+) products and isomer (-), respectively, the optically active compounds were obtained according to example 8. (+) - 5,6-dimethyl-3-propoxycarbonylmethyl-2- (3-pyridyl) -isoindolin-1-one [IUPAC Designation] : propyl (+) - 2- [5,6-d-methyl-3-oxo-2- (3-pyridinyl) -2,3-dihydro-1 H-isoindol-1-yl-acetate] Specific optical rotation [CC ] 29D = + 106.3 ° (c = 1.0, chloroform). 92 (-) - 5,6-dimetho-3-propoxycarbonylmethyl-2- (3-pyridyl) -soindolin-1-one [IUPAC name: propyl (-) - 2- [5,6- dimethyl-3-oxo-2- (3-pyridinyl) -2,3-dihydro-1 H-isoindol-1-NH-acetate). Specific optical rotation [] 29D = -101.9 ° (c = 1.0, chloroform).
EXAMPLE 31 Prepared for Invention (31 -a) Hydrochloride (15 mg) of the (-) isomer of the compound in Example 3 and sodium chloride (45.0 mg) were dissolved in distilled water for injection, and the total volume prepared was 5.0 ml. The aqueous solution was filtered under sterile conditions to give a clear injectable solution. (31-b) Hydrochloride (15 mg) of the (-) isomer of the compound in Example 3 and glucose (250.0 mg) were dissolved in distilled water for injection, and the total volume prepared was 5.0 ml. The aqueous solution was filtered under sterile conditions to give a clear injectable solution.
Pharmacological test example The anesthetic effects of the compounds of the present invention were evaluated. 93 The compounds obtained in the examples mentioned above were used. The hydrochloride salt of the compound was dissolved in saline to give the test composition. Some compounds, whose hydrochloride salts were not soluble in water, were dissolved in water in the presence of a solubilizer, hydroxypropyl-p-cyclodextrin. The respective test composition was administered to a mouse via the vein of the tail and the anesthetic effect was evaluated by the appearance and duration of the loss of the straightening reflex. The results are shown in table 9.
TABLE 9 Compound No. Activity Compound No. Anesthetic anesthetic activity Table 1 No. 2 + Table 2 No. 35 + Table 1 No. 5 ++ Table 2 No. 36 +++ Table 2 No. 1 +++ Table 2 No. 37 + Table 2 No. 2 +++ Table 2 No. 38 ++ Table 2 No. 3 ++ Table 2 No. 39 ++ Table 2 No. 4 ++ Table 2 No. 40 +++ Table 2 No. 5 ++ Table 2 No. 41 ++ Table 2 No. 6 + Table 2 No. 42 +++ Table 2 No. 7 +++ Table 2 No. 44 +++ Table 2 No. 8 +++ Table 2 No. 45 (-) ++ Table 2 No. 12 ++ Table 2 No.48 ++ Table 2 No. 13 ++ Table 2 No. 52 +++ Table 2 No. 15 + Table 2 No. 53 ++ Table 2 No. 17 +++ Table 2 No. 55 ++ Table 2 No. 20 +++ Table 2 No. 56 (-) ++ Table 2 No. 21 ++ Table 2 No. 60 + Table 2 No. 24 + Table 2 No. 62 + Table 2 No. 28 +++ Table 2 No. 63 + Table 2 No. 29 +++ Table 2 No. 66 + Table 2 No. 31 ++ Table 2 No. 67 + Table 2 No. 33 +++ Table 2 No. 68 + Table 2 No. 34 ++ Table 2 No. 87 +++ Table 3 No. 4 + Table 4 No. 5 ++ Table 3 No. 6 +++ Table 5 No. 2 + Table 3 No. 7 ++ Table 5 No. 3 ++ Table 3 No. 14 + Table 5 No. 4 +++ 94 Table 3 No. 15 + Table 5 No. 5 +++ Table 3 No. 19 ++ Table 5 No. 6 + Table 3 No. 23 ++ Table 5 No. 7 +++ Table 3 No. 27 ++ Table 5 No. 10 ++ Table 3 No. 28 (-) ++ Table 6 No. 1 ++ Table 3 No. 29 (-) + + Table 6 No. 2 ++ Table 3 No. 38 + Table 6 No.4 + Table 3 No. 39 ++ Table 7 No. 1 +++ Table 3 No. 49 (-) +++ Table 8 No. 1 +++ Table 3 No. 52 (-) ++ Table 8 No. 3 +++ Table 3 No. 54 (-) ++ Table 8 No. 4 +++ Table 3 No. 56 (-) +++ Table 8 No. 5 (-) +++ Table 3 No. 57 (4 ++ Propofol +++ Table 4 No. 2 ++ Sodium thiopental ++ The therapeutic index (A.) of the compound was determined. The HD50 value was determined, the minimum dose at which it was observed at least for 30 seconds the loss of the straightening reflex in 50% of the injected mice, and the LD50 value > the lethal dose 50%. Then the T.l. of LD50 / HD50. The results are shown in table 10. For purposes comparatives, the T.l. of intravenous anesthetics used clinically, propofol and thiopental sodium, which disclosed in published Japanese patent application No. 50-154410. 95 TABLE 10 R2 HD50 (mg / kg) LD5o (mg / kg) T.L.
Racemic Racemic CH2C-OCH2CH2CH3 27.10 > 100 > 3.69 (+) 75.35 > 120 > 1.59 (-) 20.47 > 120 > 5.86 (-) H (CH3) 2 23.07 > 120 > 5.20 (-) CH2CH2OCH2CH3 14.51 > 120 > 8.27 N (-) CH2CH2OCH2CH2CH3 14.33 > 120 > 8.37 -or Propofoi 13.5 55 4.14 Tiopental 23.5 100 4.26 sodium 96 As shown in table 10, the 50% lethal dose (LD50) of the test compound is much higher than the HD50, which is an indicator of the anesthetic action, and the maximum LD5o between the test compounds was greater than 120 mg / kg (i.v.). This means that the anesthetic composition of the invention has a very wide safety margin. Propofol and thiopental sodium, the most popular anesthetics, have much narrower safety margins. The anesthesia induction time, the time from the complete injection of the compound (2 x HD50) to the loss of the righting reflex, and the recovery time after awakening, the time since the righting reflex was normal again were determined. until the animal began to move spontaneously. The results are shown in table 11. 97 TABLE 11 Time of induction time of anesthetic recovery after Racemic 0? 3 '3'32" (-) OCH2CH2CH3 0? 2 1? 8"Propofol 0? 8! 4? 2 ' As shown in Table 11, the isoindoline derivative of the invention can provide rapid induction and recovery from anesthesia.

Claims (1)

  1. 98 NOVELTY OF THE INVENTION CLAIMS 1. - A compound represented by the formula (I): characterized in that the Ri are the same or different groups 1-3, each being selected from the group consisting of C1-3 alkyl and C1-3 alkoxy, or when the Ri are two adjacent groups, the two Ri taken together can form a 5 or 6 membered cyclic group, saturated or unsaturated, which may have 1 or 2 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen; X is oxygen or sulfur; R 2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which may be optionally substituted; provided that when R2 is phenyle, positions 3 and 4 of the fenium part are not simultaneously substituted by alkoxy groups; represents a simple link or a double link; and L is: - (CH2) n-H wherein n is an integer of 1-8; 99 - (CH ^ -N? - wherein R3 is selected from the group consisting of hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atom, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, benzyl groups , 2-pyridyl, and 2-pyrimidinyl, n 'is an integer of 1-3; - (CH 2) nCA II W wherein W is an oxygen or sulfur atom, A is selected from the group consisting of C 1-5 alkyl linear or branched, 2-dimethylaminoethylamino, 2-thiazolylamino, 4-methyIhomopiperazinyl, 4-piperadinoplperidino, dmethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonylpiperidino, 4-carboxypiperidino and a group represented by the formula (J) wherein R3 is as defined above, n "is an integer of 0-3; - (CH2) n.-C-OE II O wherein E is selected from the group consisting of hydrogen, alkenium, or C1-6alkyl linear or branched, C 1-3 alkyl substituted by at least one fluorine atom, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, 100 phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetra-idro-2H-pyranyl, cyclohexylmethyl, 1-methyl-4-piperidyl, indanyl, 1,3-benzodioxoyl and 1H-indolyl, wherein phenyl and pyridyl may be optionally substituted by the group consisting of halogen, methyl, methoxy, isopropyl and allyl, provided that when Ri is 7-methoxy and f¾ is phenyl, E is not alkyl, n "is an integer of 0-3; - (CH2) n'- T- G wherein T is oxygen, sulfur or NH, G is selected from the group consisting of hydrogen, linear or branched C 1-5 alkyl, C 1-3 alkyl substituted by at least one fluorine atom, 2-methoxyethyl and alkylcarbonyl, n 'is an integer of 1-3; where F¾ is as defined above; wherein R3 is as defined above; - (CH2) n "-C-OE wherein E is as defined above; 101 wherein R3 is as defined above; or = CH-C-OE II or where E is as defined above; or a salt of it. 2. The compound according to claim 1, further characterized in that the R < \ are two groups selected from the group consisting of methyl, ethyl and methoxy. 3. The compound according to claim 2, further characterized in that R1 is 5,6-dimethyl. 4. The compound according to claim 1, which is represented by the formula (1-1): further characterized because M represents together with the structure of isoindoline a saturated or unsaturated 5 or 6 membered cyclic group, which may optionally have 1 or 2 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen; X, R2 and L are as defined in claim 1, or a salt thereof. 102 5. The compound according to claim 4, further characterized in that M is selected from the group consisting of: -CH 2 CH 2 CH 2 -, CH 2 OCH 2 - and -OCH 20 -. 6. The compound according to any of claims 1-5, further characterized in that R2 is an optionally substituted phenyl or an optionally substituted pyridyl. 7. The compound according to any of claims 1-6, further characterized in that L is: - (CH2) -CA II W wherein W is oxygen, A is selected from the group consisting of linear C1-5 alkyl or branched and a group of the formula (J): wherein R3 is methyl or isopropyl. 8 - The compound according to any of claims 1-6, further characterized in that L is - (CH2 > - C-OE II O wherein E is selected from the group consisting of propyl, isobutyl and phenyl substituted by at least one of methyl and / or methoxy. 103 9. - The compound according to any of claims 1-6, further characterized in that L is: - (CH 2) 2 - T - G wherein T is oxygen or sulfur, G is ethyl or propyl. 10. The compound according to claim 1, which is represented by the formula: further characterized in that R2 and L are selected from the following combinations: 104 105 or a pharmaceutically acceptable salt thereof. The compound according to claim 1, which is represented by the formula: further characterized because f¾ and L are selected from the following combinations: 106 107 or a pharmaceutically acceptable salt thereof. 108 12. - The compound according to claim 1, further characterized in that it is represented by the formula where R2 is: wherein R 4 is selected from the group consisting of C 1-5 alkyl, optionally substituted phenyl and optionally substituted benzyl, and L is 13. An anesthetic composition for inducing a sedative and anesthetic effect in a mammal, comprising an anesthetic effective amount of the compound of any of claims 1-12 and a pharmaceutically acceptable carrier. 109 14. - The composition according to claim 13, further characterized because it is for intravenous injection. 15. Use of a compound of any of claims 1-12, to make a pharmaceutical composition for inducing a sedative and anesthetic effect in a mammal.
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